Menopause is an important life stage with implications for cognitive health of women. Ovarian hormones are known to regulate neuronal function beyond the neuroendocrine reproductive axis, influencing brain regions critical to cognition. However, the specific cognitive effects of gonadal steroids in woman have been difficult to define and are potentially confounded by brain health at initiation of hormone therapy (HT), as well as mood, sleep and vasomotor changes. This collaborative application combines extensive neuropsychological assessment and validated state-of-the-art neuroimaging techniques, to pilot test mechanistic hypotheses concerning the neurobiological effects of HT in healthy early postmenopausal women. To test hypotheses concerning mechanisms of gonadal steroid effects on menopausal cognitive changes, we will recruit early postmenopausal women in the age group of 45-55 years, within 12 to 24 months since their last menstrual period. Using a randomized double placebo-controlled cross-over design, 36 women will be randomized to both the treatment group (18 estradiol only, 18 progesterone only) and the order they receive 3 months of hormones and placebo. Brain functional measures will be evaluated at the end of each treatment period, in addition to hot flash and sleep monitoring and menopausal symptom assessments. The functional measures will include the performance of the volunteers on a comprehensive neuropsychological testing battery, and the brain functional responses to episodic verbal and non-verbal memory challenges, as determined with fMRI. The Specific Aims include: 1. To examine the effect of estradiol alone on brain functioning in early post- menopausal women as manifested by fMRI-BOLD activation during verbal and non-verbal cognitive tasks and 2. To determine the effects of progesterone alone on brain functioning in early postmenopausal women as manifested by fMRI-BOLD activation during verbal and non-verbal cognitive tasks. PUBLIC HEALTH RELEVANCE: These studies will determine the differential contributions of estrogen and progesterone to cognitive processing in early postmenopausal women. A better understanding of the specific contributions of gonadal sex hormones to brain processing changes will allow for preparation of an R01 to comprehensively study the neurobiology of hormone use in early menopause and will ultimately allow the health community to plan interventions which may most effectively preserve cognitive health for women.